Traumatic brain injury (TBI) is a major cause of premature death and disability worldwide. Few effective treatments exist. Based on encouraging results from studies with animals, we hypothesize that early administration of progesterone to victims of moderate to severe TBI reduces secondary brain injury and improves neurological outcomes. Prior to proceeding with a full-scale clinical trial, we propose to conduct a pilot study by identifying and recruiting eligible subjects at a single level I trauma center. Consenting subjects will be randomly assigned to receive either IV infusion of progesterone or an equivalent volume of placebo. The study team, which will be blinded to treatment status, will monitor each subject's clinical progress and assess outcome at one month post-injury. The primary objectives of this pilot study are to: 1) achieve proper dosing of the study drug, 2) gather data on drug safety, and 3) generate preliminary evidence of efficacy. The secondary objective is to identify the most appropriate clinical subgroup(s) for subsequent treatment in a multi-center trial. To identify the correct dosage and infusion rate to achieve a steady state serum progesterone concentration (SSSPC) level of 450 nmole/L + 100 in our subjects, we will statistically examine the SSSPCs of the first ten subjects randomized to progesterone. To test the safety of the progesterone infusion, we will monitor patients for several unlikely, but potential complications of progesterone administration. To assess the potential efficacy of the progesterone for TBI, we will compare treatment groups with respect to duration of coma, death at one month post-injury, and most important, neurological outcome at one month post-injury. Three measures of neurological outcome will be used: the Glasgow Outcome Score, the Disability Rating Scale, and the Galveston Orientation and Amnesia Test. Once these objectives are accomplished, we will apply the lessons learned in this pilot study to mount a multi-center, randomized, double blind, placebo-controlled clinical trial of intravenous progesterone for treatment of traumatic brain injury. If the therapeutic benefits observed in animals are replicated in humans, administration of intravenous progesterone should produce several benefits, including: a) decreased duration of coma; b) decreased mortality; and c) improved neurological function. If these hypotheses are verified, this it will represent a major advance in the treatment of traumatic brain injury.